NIH Summary: Modern sequencing technologies now enable detailed measurements of germline and somatic alterations, many of which underly human disease. An enormous amount of human genetic data has been collected, and understanding the breadth and complexity of human variation presents one of the greatest scientific challenges of our time. In particular, interpretation of genetic variation and its relevance to disease is critical for the success of precision medicine programs. Addressing this challenge will require that researchers and clinicians from many diverse disciplines work together. Our scientific program includes talks from systems biologists, genomic scientists, computer scientists, molecular biologists, medical geneticists, population geneticists, data scientists, oncologists, biophysicists, and experts in health informatics. We will focus on how we can combine our expertise to understand the complex nature of the association between human genetic variation and disease and promote translation of that knowledge into clinical practice. Computer and data science, molecular biology, biophysics and population genetics can provide independent sources of information about genetic variants. Variants can be characterized by their locations in genomic DNA, evolutionary, physico-chemical, structural, and functional properties, their effects on RNA transcripts, proteins, molecular interactions, and ultimately their impacts on human cells and tissues. For many diseases, the molecular mechanisms of pathogenesis have not yet been characterized and innovative methodologies can contribute to future progress. The meeting features sessions on new computational approaches for interpreting non-coding and structural variants and on emerging technologies for ribosome profiling, microbiome analysis, and single-cell sequencing and mass cytometry. In addition, advances in health informatics, medical genetics, and clinical practice are critical to the translational impact of basic research. By fostering close interactions and active discussion among practitioners from these many disciplines, we will foster leadership for the coming decade of rapid progress in research and applications relevant to human genetic variation and disease.